Method and device for in-situ formulation of a medicinal solution for parenteral application

ABSTRACT

Method for the in situ formulation of a medicinal substance solution for parenteral administration, in which at least two metered part-streams are continuously combined with the aid of a mixer to an active ingredient-containing total volumetric flow, characterized in that the resulting medicinal substance solution is not in thermodynamic equilibrium, and in that the resulting total volumetric flow after mixing is 0.2 ml/h to 500 ml/h, preferably 5 ml/h to 500 ml/h, an apparatus for carrying out the method, and an active ingredient administration kit which contains the apparatus.

The aim of developing infusion solutions which can be administeredintravenously is always good tolerability of the preparation. To ensurethis it is necessary for the formulation to be approximated as closelyas possible to physiological circumstances, that is to say it should bein the form of an aqueous formulation with isotonic (osmolarity) andisohydric (pH) properties.

Some active pharmaceutical ingredients have the disadvantage that theyare difficult to formulate or convert into a form ready for use owing totheir low solubility, sensitivity to hydrolysis or oxidation or owing totheir photosensitivity. This can in the final analysis be attributed tothe fact that the active ingredients are not in thermodynamicequilibrium under usual formulating conditions, that is to say that theyeither precipitate or decompose under physiological conditions. Thus theformulation possibilities and, in the final analysis, the provision ofsuch active ingredients are greatly restricted.

Active pharmaceutical ingredients, especially those of the more recentgeneration, often have the disadvantage of low solubility in aqueousmedium at physiologically tolerated pH values. This applies inparticular to active ingredients from the group of dihydropyridines,anaesthetics, antibiotics, antimycotics, immunosuppressants, CNS-activedrugs, oncologicals, steroids, barbiturates and vitamins. Slightlysoluble active ingredients have, according to the definition in currentpharmacopoeias, a solubility in water of less than 1 percent by weight.Slightly soluble active ingredients frequently confront thepharmaceutical technologist with the problem of developing asufficiently well tolerated aqueous infusion solution when the volumeadministered by infusion is strictly limited. The patient in particularin intensive care units (ICU) frequently receives several infusionsolutions administered in parallel, in which case the acceptable dailyvolume depends on the kidney function of the individual. One priority ofpharmaceutical development is to minimize the infusion volume, thisparameter showing a contrary behaviour to the solubility of thesubstance. Formulating additions such as isotonicizing agents,antioxidants etc. moreover reduce the dissolving capacity of water. Theactive ingredient also frequently has a solubility or stability optimumoutside the physiological pH range of 7.2-7.6, so that the formulationpossibility is further restricted at the optimum pH.

Because of the poor solubility in aqueous media, the active ingredientis dissolved in an organic or aqueous/organic solvent or at stronglyacidic/alkaline pH values in aqueous or aqueous/organic medium (activeingredient concentrate). In order to ensure tolerability, administrationof this active ingredient concentrate must be preceded by dilution withan aqueous medium (diluting medium) or adjustment to physiologicallytolerated pH values. This may result in supersaturated solutions. Theseare characterized in that the dissolved active ingredient is present ina concentration higher than is possible in the solvent at the giventemperature by dissolving the active ingredient crystals. Such solutionsare, as a consequence of the kinetic inhibition of crystallization,initially optically clear and virtually free of particles. However, thesolutions are thermodynamically unstable. Thus, over the course of time,they lead to the active ingredient crystallizing out and thus particlesbeing formed. Since relatively long times, which include at least theduration of the infusion, frequently elapse for example afterpreparation of such solutions in hospitals until they are completelyinfused into the patients, formation of particles in the solution ispossible during this. Particles injected into the bloodstream may,however, depending on their size and shape lead inter alia to vascularocclusion and thus to serious harm to the patient. This risk can bereduced either by ensuring the stability of the supersaturation alsoover a lengthy period and under all environmental conditions,demonstrating this with certainty, or by minimizing the time thesupersaturated solution stands after its preparation. The latter objectis achieved by the present invention, namely by preparing thesupersaturated solution from an active ingredient concentrate and adiluting medium with use of a special mixer immediately beforeadministration—on the patient's arm—and only seconds up to a few minuteselapsing until the solution enters the bloodstream.

On simultaneous parenteral administration of different solutions byintravenous infusion so-called connecting pieces or Y pieces (forexample Codan Art. No. C87/2R) have been used to date. Connection toother infusion equipment takes place, for example, via so-calledLuer-Lock connectors complying with DIN 13090 Part 2 (disposable medicalarticles: medical products; standards and other documents; Beuth Verlag1989). The infusion solutions having viscosities in the region of a fewmPas are fed from different containers to the relevant connecting pieceand combined therein simply by being conducted together before themixture reaches the patient. An infusion device of this type isdescribed, for example, in DE-3228595-C2. In this case, 2 solutions frominfusion bottles are combined by gravity through a Y piece and infused.Disposable articles of this type are commercially available in a varietyof forms. The disadvantage of the available devices is that it isimpossible to mix fluid media with very different viscosities at theavailable low flow rates (5-500 ml/h) sufficiently and quickly enoughbecause the commercially available connecting pieces are not optimal interms of their function as mixers. In particular at low flow velocitiesthere is sometimes a back-flow of the solutions, and components of thesolution spend some time in regions of low flow (dead spaces). This canlead to crystallization inside the administration system. Organicsolvents which can be administered parenterally may have viscositiesabove 100 mPas (for example macrogol 400). When the organic activeingredient concentrate and the aqueous diluting medium are mixed thereis a risk that the active ingredient will crystallize out of thesupersaturated solution after a certain time. The time up to the onsetof crystallization decreases with increasing content of aqueous phase.However, at the same time, the tolerability increases with increasingcontent of aqueous phase.

The result of the problems described is that no suchconcentrate/dilution systems have yet been developed for a marketableproduct. On the contrary, the only solution presentations marketed arethose whose system is not supersaturated. This is achieved, for example,by adding relatively large amounts and relatively high concentrations oforganic solvents (ethanol, macrogol, propylene glycol etc.) orsolubilizers and surfactants (Tween, Cremophor), which have an adverseeffect on the local and systemic tolerability of the formulation.

GB-A-1472793 describes such formulations for the anaesthetic propofol,in which surface-active substances and water-miscible, nonaqueoussolvents are added to the aqueous base. A concentration of 20-30% oforganic medium should not be exceeded as limits for the localtolerability of organic solvents in infusions. The systemic tolerabilityof the solvents varies in a substance-specific manner. In general,solvents lead to irritation and inflammation of veins and to haemolysis.Surfactants have even stronger haemolytic activity and, moreover, maycause an anaphylactic shock reaction with a fatal outcome. It istherefore necessary to examine such formulations particularlycritically, and a precondition for a decision in their favour is anappropriate benefits/risk assessment.

Another possibility, for which the possible uses are, however, onlylimited, is to develop presentations such as, for example, lipidemulsions or liposome formulations, but these are considerably morecomplicated and thus more costly than conventional solutionformulations. The formulation of oil-in-water emulsions for the activeingredient propofol is likewise described in GB 1 472 793 andfurthermore in DE-19 509 828-A1. Further examples of slightly solubleactive ingredients are to be found in U.S. Pat. No. 4,168,308. Theproduction of aqueous liposome dispersions as a possible formulation ofslightly soluble medicinal substances is described in EP-A-0 560 138 foractive ingredients of the dihydropyridine class. This makes theconsiderable technical complexity of these alternative formulationsclear.

If such formulation problems become evident, frequently no developmentof slightly soluble active ingredients is carried out, or thedevelopment times for a formulation become markedly prolonged.

It is an object of the invention to provide a method with which it ispossible to administer slightly soluble active ingredients in a simplemanner and, at the same time, distinctly reduce the amount andconcentration of excipients necessary (solvents, surfactants etc.) forthe formulation by comparison with conventional formulations, or makethem entirely unnecessary. The intention is furthermore to provide anapparatus with which it is possible to mix an active ingredientconcentrate in a very short time completely with a diluting medium sothat the active ingredient can reach the patient's vein in dissolvedform. The mixing apparatus to be developed for this purpose must meetadditional requirements: the construction material chosen is expedientlyone which can be sterilized and with which no attrition takes place. Theflow pathways are expediently designed and dimensioned so that noregions of low flow (dead spaces) result and the flow velocities producevigorous mixing in the mixing apparatus even at low flow rates. In orderto ensure that the infusion solution spends a short time between themixing apparatus and the patient, the mixing apparatus should beattached in the vicinity of the infusion site. The pressure prevailingin the mixing apparatus should not exceed 1 bar.

The invention therefore relates to a method for the in situ formulationof a medicinal substance solution for parenteral administration, inwhich at least two metered part-streams are continuously combined withthe aid of a mixer to an active ingredient-containing total volumetricflow, characterized in that the resulting medicinal substance solutionis not in thermodynamic equilibrium, and in that the resulting totalvolumetric flow after mixing is 0.2 ml/h to 500 ml/h, preferably 5 ml/hto 500 ml/h.

A medicinal substance solution which is not in thermodynamic equilibriumwithin the meaning of the invention is a solution which, under theadministration conditions, has a tendency to undergo a transition with achemical or physical change into a lower-energy state. Such a chemicalor physical change may consist of, for example, the active ingredientdecomposing, for example through hydrolysis, oxidation or photolysis, orbeing precipitated. The formulation of the medicinal substance solutionby combining the metered part-streams in the method of the inventiontakes place in such a way that the resulting medicinal substancesolution is subject to no change compromising administration until itenters the human body.

In a preferred embodiment of the method, the two part-streams arecombined in a mixing chamber volume of 0.2 μl to 2 μl, preferably 0.4 μlto 1.5 μl.

In another preferred embodiment of the method of the present invention,the metered part-streams comprise at least one activeingredient-containing solution and at least one active ingredient-freediluting medium, and the resulting solution, which is not inthermodynamic equilibrium, is a supersaturated medicinal substancesolution.

The active ingredient-containing solution is preferably an organic oraqueous organic active ingredient concentrate, and the activeingredient-free diluting medium is an aqueous or aqueous organicdiluting medium.

The active ingredient concentrate is formulated using suitablewater-miscible organic solvents, mixtures thereof or mixtures withwater, in each of which the particular active ingredient dissolvesespecially well. Preferred organic solvents are macrogols of variousmolecular weights, 1,2-propylene glycol, ethanol, glycerol, glycofurol,2-pyrrolidone and glycol ethers. It is possible to add furtherexcipients such as stabilizers (surfactants, complexing agents) orantioxidants, isotonicizing agents, agents to adjust the pH, inter alia,to the active ingredient concentrate. However, it is preferred not toadd stabilizers or at least to considerably reduce the amount thereof.It is possible by choosing the optimal solvent advantageously to reducethe total amount of organic solvent required. The active ingredientconcentrate should not exceed a viscosity of 500 mPas and is preferablyin the range 50-150 mPas, in order to ensure the function of the mixer.Solvents of higher viscosity such as glycerol and higher molecularweight macrogols are therefore mixed with lower viscosity solvents suchas ethanol, water, 1,2-propylene glycol or others.

The active ingredient concentrate is diluted using diluting media. Theseare water, physiological saline or other electrolyte solutions such asRinger solution, Ringer lactate solution etc., glucose-, sorbitol-,mannitol- or other carbohydrate-containing solutions, volume replacementsolutions (dextrans and derivatives thereof, gelatin and derivativesthereof, starch derivatives), serum derivatives and combinations oraqueous organic solvent mixtures with solvent concentrations of lessthan 30%, preferably less than 10%. Suitable solvents are thewater-miscible solvents already mentioned, such as macrogol of varyingmolecular weight, 1,2-propylene glycol, ethanol, glycerol, glycofurol,2-pyrrolidone and glycol ethers. It is possible to add furtherexcipients such as stabilizers (surfactants, complexing agents) orantioxidants, isotonicizing agents, agents to adjust the pH, inter alia,to the diluting medium. However, it is preferred not to add stabilizersor at least to considerably reduce the amount thereof. The viscosity ofthe diluting medium is preferably in the range 1-10 mPas, because thisreduces the viscosity of the complete mixture and that of blood isapproached.

For the purpose of the present invention, the supersaturated medicinalsubstance or active ingredient solution formed on mixing the activeingredient concentrate and diluting medium contains more dissolvedactive ingredient than the maximum amount of active ingredient which canbe taken up by a solution of the same volume in thermodynamicequilibrium at the same temperature. The latter is the solubility of theactive ingredient in the resulting infusion solution at the giventemperature.

The result of mixing active ingredient concentrate and diluting mediumis an infusion solution of the desired concentration, in which theactive ingredient is present in dissolved but supersaturated form anddoes not crystallize out over the period from mixing until entry intothe vein. In the vein there is rapid dilution by the bloodstream andbinding to plasma proteins, which acts to counter crystallization of theactive ingredient there. The concentration of solvents in the completesolution can be reduced to distinctly less than 30%, and in some casesto 7%, leading to the expectation of good local tolerability. At thesame time, the total volume of the infusion solution and thus the totalamount of organic solvent and other excipients is kept low.

In a further embodiment of the invention, the activeingredient-containing solution is an aqueous or aqueous organic activeingredient concentrate, and the active ingredient-free diluting mediumis an aqueous or aqueous organic diluting medium, the pH values of whichare matched together so that the total volumetric flow resulting afterthe mixing has a physiologically tolerated pH in the range from 3 to 10,preferably 5-8.

This embodiment is used in cases where the active ingredient has apH-dependent solubility or stability, and the solubilities orstabilities are good only in nonphysiological pH ranges below pH 3 andabove pH 10. An appropriately acid or alkaline aqueous or aqueousorganic active ingredient concentrate is then prepared.

It is preferable to add to the active ingredient concentrate furtherexcipients such as stabilizers (surfactants, complexing agents,solubilizers), water-miscible organic solvents or antioxidants,isotonicizing agents, buffering agents and others. However, it ispreferred not to add stabilizers and organic solvents or at least toconsiderably reduce the amount thereof.

Aqueous diluting media whose pH has in each case been adjusted tocounter the active ingredient concentrate are used to dilute the acidicor alkaline active ingredient concentrate. These diluting media arewater, physiological saline or other electrolyte solutions such asRinger solution, Ringer lactate solution etc., glucose-, sorbitol-,mannitol- or other carbohydrate-containing solutions, volume replacementsolutions (dextrans and derivatives thereof, gelatin and derivativesthereof, starch derivatives), serum derivatives and combinations oraqueous organic solvent mixtures with solvent concentrations of lessthan 30%, preferably less than 10%. Suitable solvents are thewater-miscible solvents already mentioned, such as macrogol of varyingmolecular weight, 1,2-propylene glycol, ethanol, glycerol, glycofurol,2-pyrrolidone and glycol ether. It is possible to add further excipientssuch as stabilizers (surfactants, complexing agents) or antioxidants,isotonicizing agents, buffering agents, inter alia, to the dilutingmedium. However, it is preferred not to add stabilizers or at least toconsiderably reduce the amount thereof. The viscosity of the dilutingmedium is preferably in the range 1-10 mPas, because this reduces theviscosity of the complete mixture and that of blood is approached.

The combination of the active ingredient concentrate and diluting mediumresults in the pH of the complete solution being maintained atphysiologically tolerated pH values in the range from 3 to 30,preferably in the range from 5 to 8.

The method of the invention is particularly suitable for theadministration of active ingredients having a solubility of less than 1%by weight in water at 20° C.

The active ingredient is preferably selected from the group consistingof dihydropyridines, anaesthetics, antibiotics, antimycotics,immunosuppressants, CNS-active drugs, oncologicals, steroids,barbiturates and vitamins.

Examples of such active ingredients are paclitaxel, docetaxel orsubstances related thereto, or ciclosporin.

The method is implemented by employing a mixer which preferably has nodead spaces and particularly preferably is miniaturized and has no deadspaces. The time spent by the mixture in the mixer and mixing section isexpediently less than 1 min, preferably less than 30 s. The mixerexpediently used is a nozzle mixer in which each of the part-streams ispassed through a nozzle with a hydraulic diameter between 1 μm and 500μm, preferably between 100 μm and 250 μm, and then collide with velocitycomponents in opposite directions in a mixing chamber, and the mixturewhich forms is conveyed away as total volumetric flow. The totalvolumetric flow is expediently conveyed away through at least oneaperture downstream of the mixing chamber. The nozzle diameter isexpediently chosen so that the flow velocity in the nozzles is 0.01 to15 m/s, preferably 0.01 to 3 m/s.

The invention furthermore relates to an apparatus for the in situformulation of a medicinal substance solution for parenteraladministration, having at least two feed lines, in each of which areservoir and a metering device are connected in series, and the feedlines open downstream of the metering devices into an infusion line,characterized in that the feed lines are connected to a nozzle mixerwhich consists of a mixing chamber connected to the infusion line and oftwo nozzles which are disposed in the feed lines, are opposite to oneanother and open into the mixing chamber.

The mixing chamber has a volume of, preferably, 0.2 μl to 2 μl,particularly preferably of 0.4 μl to 1.5 μl, and the nozzles have ahydraulic diameter of, preferably, 1 μm to 500 μm, particularlypreferably of 100 μm to 250 μm.

It is expedient for a homogenizing aperture with a hydraulic diameter of1 to 500 μm, preferably 100 to 250 μm, to be disposed at the outlet fromthe mixing chamber.

The flow pathways within the two feed lines, including the meteringdevices and the nozzles, are preferably designed symmetrically.

The nozzle mixer preferably consists of an injection-mouldable plastic,particularly preferably of polycarbonate. When the apparatus accordingto the invention is used with photosensitive active ingredients, asubstance which ensures adequate protection from light even with thinmixer walls can be admixed with the plastic. The substance isexpediently selected in this case so that it effectively shields fromthe wavelength range in which the photosensitive active ingredient isdecomposed.

The invention furthermore relates to an active ingredient administrationkit for carrying out the method according to the invention, consistingof a pack with the apparatus according to the invention and of areservoir at least for the active ingredient concentrate. The activeingredient administration kit preferably additionally contains tubinglines for the connections to the apparatus (mixer) and to the meteringdevices. Concerning the active ingredients, the active ingredientconcentrates and the diluting media, reference may be made to thestatements above.

The invention is described in detail hereinafter by means of exemplaryembodiments and drawings. These show:

FIG. 1 a basic procedure diagram for carrying out the formulation methodaccording to the invention for parenteral administration,

FIG. 2 a preferred embodiment of a nozzle mixer for mixing andhomogenizing an active ingredient concentrate and a diluting medium,

FIGS. 3-5 further embodiments of the nozzle mixer and

FIG. 6 an experimental apparatus for carrying out the exemplaryembodiments described hereinafter.

In the embodiment shown in FIG. 1, the active ingredient concentrate (1a) and the diluting medium (1 b) are fed by syringe drivers or infusionpumps (4 a, 4 b) through the tubing connectors to the apparatus (3). Themixture (5) is fed immediately after the mixing in the apparatus (3)according to the invention, and after passing through the connectingtubing (6) and, where appropriate, a filter (7) and the injection needle(8), to the patient.

Instead of these syringe drivers or infusion pumps it is also possibleto employ other suitable systems such as, for example, two separatesyringes which are connected to the mixing apparatus and are operatedmanually, for example for administering a bolus injection. In this case,the maximum flow rate of the part-streams and the maximum pressure inthe system essentially depend on the manually applied force, it beingnecessary to take account of the tolerability of the administration.

The embodiment of the apparatus according to the invention shown in FIG.2 consists of at least one nozzle (9 a or 9 b) and of a homogenizingaperture (10) downstream in the direction of flow, which can be in anysuitable relative geometric arrangement, of a mixing chamber (11) and ofa mixing section (12). The connecting tubing (6) can also serve asmixing section. The nozzles (9) disperse the respective starting fluids(1 a, 1 b) and feed them to the mixing chamber (11). The task of thedownstream aperture (10) is to homogenize the resulting mixture. Themixing section (12) serves additionally to ensure complete mixing beforethe mixture is injected into the patient. Two opposing nozzles (9 a, 9b) are preferably used for mixing two fluids (FIG. 2); the homogenizingaperture (10) is dispersed perpendicularly and symmetrically withrespect to the nozzles (9 a, 9 b) on the mixing chamber (11). Anessential precondition for achieving the required object of mixing is tominimize the mixing chamber volume (mixing chamber (11)) between nozzles(9 a, 9 b) and homogenizing aperture (10) in order to maximize theenergy input per volume. Thus, miniaturized construction of the completeapparatus is particularly suitable. The total void volume is, forexample, 0.5 μl. The orifices of the nozzles and of the aperture have adiameter between 0.001 and 0.5 mm, preferably 0.25 mm. The totalpressure drop is then, with fluid velocities in the nozzles of 0.1 m/sto 15 m/s, less than 1 bar. An apparatus according to the invention isfabricated in a flat design preferably from polycarbonate and preferablyhas edge dimensions of 1 cm×1 cm×0.4 cm (L×B×H), so that it can in themethod according to the invention be attached without difficulty in thedirect vicinity of the injection site on the patient (adhesive plaster).For stabilizing the apparatus when attaching to the patient's arm it isadditionally possible to provide so-called wings on the housing of theapparatus. An in-line arrangement was chosen for the tubing connectionsin order to reduce the mechanical stress on the housing of theapparatus. Appropriate standardized Luer-Lock connections can beattached at the ends of the tubing for connecting the apparatusaccording to the invention to syringe drivers or infusion pumps whichconvey in each case the initial fluids to be mixed.

A further embodiment of the apparatus according to the invention whichis depicted in FIG. 3 provides for feeding only one fluid, that of lowviscosity, through a nozzle (9) which is arranged opposite thehomogenizing aperture (10); however, in principle, all geometricarrangements can be implemented. Thus, it is possible because of theminiaturized construction for any number, but preferably less than 10,initial fluids to be fed to the apparatus, as depicted in FIG. 4 and inFIG. 5 by way of example for a total of four initial fluids (1 a-1 d).The embodiment shown in FIG. 5 is preferably used. The high degree ofintegration makes it possible easily to replicate many times the basicstructure in the apparatus according to the invention (FIG. 5).

The method according to the invention, including the apparatus accordingto the invention, has the advantage that supersaturated infusionsolutions can be prepared reliably and reproducibly and be administeredimmediately after preparation. This dispenses with the problems of thestability of the prepared infusion solution, which must amount toseveral hours in hospital procedures, so that it is possible for thefirst time also to perform intravenous administrations of supersaturatedsolutions of slightly soluble active ingredients routinely in hospitalprocedures. The direct administration makes it possible to achieve adistinctly reduced concentration and absolute amount, compared withconventional solutions, of solvents which impair the tolerability of thesolution. There is also the potential to dispense with particularorganic solvents (for example ethanol) in the infusion solution. Thismight make it possible to extend the market for some infusion solutionsto countries in which the relevant solvent is not approved forparenteral administrations (for example Japan: ethanol). It is alsopossible to dispense with excipients which are normally added to theinfusion solution for stabilization, or at least distinctly reduce thecontent thereof.

The apparatus according to the invention can be injection moulded,resulting in the possibility of economic mass production.

It is possible with the aid of the apparatus to mix very rapidly andcompletely fluids differing considerably in viscosity. This avoids localsupersaturation occurring for lengthy periods, which would result inprecipitation of the active ingredient. Local increases in theconcentration of organic solvent, which may damage blood vessels,likewise do not occur.

In order to avoid damage to blood vessels it is necessary for the activeingredient concentrate to be homogeneously mixed in the diluting medium.Hence checking the mixing is an essential aspect for characterizing theapparatus according to the invention.

The experimental apparatus depicted diagrammatically in FIG. 6 was usedto demonstrate the operability of the method according to the inventionand apparatus according to the invention. The various types of mixerindicated in the following table were used for this:

Diameter Volume of the Nozzles Aperture mixing chamber Mixer type μm μmμl A 100 100 0.5 B 250 250 1.5 C CODAN Article No. C87/2R

The experimental apparatus consists of two identical trains which makeit possible to compare the apparatus according to the invention (3:mixer type A and B) directly with a conventional connecting piece (17:mixer type C). The active ingredient concentrates (1 a, 1 c) are fedwith the aid of Perfusor pumps (use of 50 ml Perfusor syringes) throughthe tubing lines 2 a, 2 c (internal diameter 2 mm) to the apparatus (3)and the connecting piece (17). The metering of the diluting media (1 b,1 d) likewise takes place through Perfusor pumps and tubing lines (2 b,2 d). The mixtures (5 a, 5 b) leave the apparatus (3) and the connectingpiece (17) and pass directly into the glass tubes 14 a and 14 brespectively (internal diameter 1.8 mm). The mixtures leave the glasstubes and are passed through tubings (15 a, 15 b) into collectionvessels (16 a, 16 b).

To assess the mixed materials, an organic solvent approved forparenteral administration and having a viscosity of 100 mPas (macrogol400) was used, specifically without active ingredient. The solvent wasacidified with a few drops of HCl, and the diluting medium water (about1 mPas) was made basic with NaOH and coloured red with phenolphthalein.The ratios of amounts were chosen so that decolorization occurred at theparticular ratio of amounts of water and solvent. The colour change ofthe indicator used takes place between pH 8 and pH 10. Assessment of themixed materials was based on the decolorization behaviour and the visualcheck of homogeneous phase mixing, and after what distance in the glasstubes (14) decolorization or homogeneous mixing is found.

Besides ensuring homogeneous mixing of active ingredient concentrate anddiluting medium, a further aim was to ensure that no active ingredientcrystallizes out within a particular time and with a large content ofdiluting medium in the infusion solution. This was done by preparingvarious active ingredient concentrates, which were then mixed with thediluting medium in the manner described above in the apparatus (3)according to the invention. It was firstly found, by observing themixture (5 a) in the glass tube (14 a), whether visible particles werepresent in the mixture (for example crystallization from supersaturatedsolution). If this was not the case, the mixture (5 a) was passedimmediately downstream of the apparatus (3) which had previously beendetached from the glass tube, into a measuring vessel, and the particledistribution (HIAC) was determined. A sample volume of 10 ml was neededfor this. Sampling and preparation for the measurement take about 10min. This ensures that the mixture stands for at least 10 min, which isthe maximum time between mixing and entry into the patient in oneembodiment of the method according to the invention. The particle countsindicated in the tables for the respective examples were obtained byaveraging three measurements. This made it possible to check whether themaximum particle concentrations specified in the pharmacopoeias (USPXXIII: The United States Pharmacopeia Jan. 23, 1995) were not exceeded.It is appropriate to use various types of apparatuses in order to ensuresufficiently good mixing in the entire volumetric flow range. The typesdiffer in the diameter of the nozzles and apertures (see table above).Moreover, only nozzles and apertures with a uniform diameter areinitially used in an apparatus. However, it is also possible for thediameters of nozzles and apertures to be individually adjusted dependingon the mixing problem so that there are also nozzles or apertures withdifferent diameters in a particular apparatus. The various exemplaryembodiments are described below.

EXAMPLE 1 Experiments for the Assessment of the Mixing Materials

In the case of the apparatuses according to the invention (mixer type Aand B) it emerged that the mixture (5) was already decolorized afteremergence from the homogenizing aperture (10). Homogeneous mixing of thephases took place after passing through a mixing section (11) of amaximum of 20 mm in 0.4 and 17 seconds. After this time had elapsed,complete mixing of solvent and diluting medium is to be expected, thusavoiding vascular damage in the patient.

Volu- Volu- metric metric Decolorization Mixing flow Diluting flow Mixersection²⁾ section²⁾ Time³⁾ Solvent [ml/h] medium [ml/h] type mm mm sPEG¹⁾ 1 water 10 A 0 ≦20 ≦17.00 PEG¹⁾ 30 water 75 B 0 ≦20 ≦1.80 PEG¹⁾ 30water 400 B 0 ≦20 ≦0.43 PEG¹⁾ 1 water 10 C >600 ≧600 ≧500.00 PEG¹⁾ 30water 75 C >600 ≧600 ≧53.00 PEG¹⁾ 30 water 400 C >600 ≧600 ≧13.00 ¹⁾PEG:macrogol 400; ²⁾pathway in the glass tube with a diameter of 1.8 mm (seeFIG. 6, 14a and 14b); ³⁾time spent in the glass tube until mixing ishomogeneous.

In the case of the commercially available connecting piece (mixer typeC), no mixing of diluting medium and solvent was detectable. Two streamsof fluid, one coloured (diluting medium) and the other colourless(solvent), ran virtually through the entire glass tube (L=600 mm). Insome regions of the glass tube there was partial turbulence of thestreams of fluid without decolorization; complete mixing was notobserved in this case.

EXAMPLE 2 Formulation of an Antibiotic of the Oxazolidinone Class (Bay17-1648) with Glycofurol as 2% Strength Active Ingredient Concentrate

The daily dose of the antibiotic Bay 17-1648((5S)-3-(3-methyl-2-benzothiazolinon-6-yl)-5-(propionylaminomethyl)oxazolidin-2-one,EP 738726) is about 1000 mg. The following data were found for thesaturation concentration (M/V) at 20° C.:

Volume of solvent Dynam. viscosity Saturation per dose Solvent [mPas]concentration (1000 mg) Water (W) 1 0.045% 2222 ml (45 mg/100 ml)Propylene glycol 60 0.7% 143 ml (PG) (700 mg/100 ml) Macrogol 400100-130 1.6% 63 ml (PEG) (1600 mg/100 ml) Glycofurol (GF) about 50 2.2%45 ml (2200 mg/100 ml)

Taking the saturation concentrations as the basis for the formulations,the required volume of solvent for the daily dose of 1000 mg is at least2222 ml W, 143 ml PG, 63 ml PEG or 45 ml GF. Since for a stableformulation it is necessary to keep a safety margin from the saturationconcentration in order to ensure low-temperature stability as well, thesolvent volumes mentioned are the lower limit for a conventional solventformulation.

It is possible with GF to formulate a 2% strength active ingredientconcentrate which must be diluted before use in order to be sufficientlywell tolerated. The mixture ready for use with a maximum concentrationof 20-25% GF requires, for administration in the hospital, physicalstability in respect of crystallization for at least 6 h. Dilutionexperiments carried out in a conventional way with aqueous media withoutthe use of the method according to the invention and the apparatusaccording to the invention showed the following result:

Solvent concentration 25% GF 20% GF Diluting medium water 20% strengthglucose solution Active ingredient ca. 200 mg/100 ca. 100 mg/100 ml(0.1%) saturation conc. in CM ml (0.2%) Active ingredient 500 mg/100 ml400 mg/100 ml (0.4%) concentration in CM (0.5%) Supersaturation in CMca. 2.5-fold ca. 4-fold Amount of solvent per 50 g/1000 mg 50 g/1000 mgdose Crystallization after 1-2 h after 1 h The 20% strength GF solutionwas poorly tolerated in animal experiments

On use according to the invention of the mixing apparatus, 50 ml of 2%strength active ingredient concentrate (GF) and 667 ml of water (ratio1:13) are combined by means of a Perfusor pump for the concentrate andinfusion pump for the diluting medium through the apparatus so that atotal volumetric flow of 430 ml/h is reached. This reduces theconcentration of the organic solvent glycofurol in the complete mixtureto 7%. The infusion volume needed to administer the daily dose of 1000mg of Bay 17-1648 in this case is 717 ml/day. The infusion time in thiscase is about 100 min per 1000 mg of Bay 17-1648.

The saturation solubility of Bay 17-1648 with 7% GF in water is about 20mg/100 ml. Compared with this value, the mixture ready for use is about7-fold supersaturated at 140 mg/100 ml. As the particle measurementsshow, the formulation is stable to crystallization for at least 1 min.

Mixer type — B Inlet pressure: diluting medium (DM) mbar 100 Inletpressure: active ingredient mbar 120 concentrate (AC) Solventconcentration (CM) g/100 ml¹⁾ 7 Active ingredient concentration in theg/100 ml²⁾ 2 solvent Total amount of infused solvent ml 50 Dilutingmedium — water Volume of the complete mixture (CM) ml 717 Metering rate(total active ingredient mg/min 1000 mg/ dose) 100 min Volumetric flowCM ml/b 430 Flow velocity: AC nozzle m/s 0.17 Flow velocity: DM nozzlem/s 2.26 Flow velocity: CM aperture m/s 2.43 Particle count ≧ 10 μm[max. 25/ml] Particle count/ml 19 Particle count ≧ 25 μm [max. 3/ml]Particle count/ml 1 ¹⁾Mass of solvent based on 100 ml of completesolution; ²⁾Mass of active ingredient based on 100 ml of solvent (activeingredient concentrate).

Whereas it was not possible to achieve adequate stability tocrystallization of the mixture ready for use and satisfactorytolerability of the solution in the experiment on formulation of aconventional solvent formulation, the use according to the invention ofthe method and the apparatus made well-tolerated parenteraladministration of the active ingredient possible.

EXAMPLE 3 Formulation of an Antibiotic of the Oxazolidinone Class (Bay17-1648) with Macrogol 400 as 1.5% Strength Active IngredientConcentrate

The saturation solubility of the antibiotic Bay 17-1648 in macrogol 400(PEG) permits, in analogy to Example 2, the formulation of a 1.5%strength active ingredient concentrate which must likewise be dilutedbefore use. The mixture ready for use with a maximum concentration of30% PEG requires, for administration in the hospital, physical stabilityin respect of crystallization for at least 6 h. Dilution experimentscarried out in a conventional way with water without the use of themethod according to the invention and the apparatus according to theinvention showed the following result:

Solvent concentration 30% PEG 17% PEG 10% PEG Diluting medium waterwater water Active ingredient 150 mg/100 ml 100 mg/100 ml 80 mg/100 mlsaturation conc. in CM (0.15%) (0.1%) (0.008%) Active ingredient 450mg/100 ml 250 mg/100 ml 150 mg/100 ml concentration in CM (0.45%)(0.25%) (0.15%) Supersaturation in CM 3-fold 2.5-fold ca. 2-fold Amountof solvent 66.7 g/1000 mg 68 g/1000 mg 66.7 g/1000 mg per doseCrystallization after 24 h after 1 h after 1 h

The 30% strength solvent concentration shows marginal local tolerabilityin animal experiments. Lower solvent concentrations show distinctly lessstability to crystallization. It was moreover difficult, owing to therelatively high viscosity of the solvent, to obtain a homogeneoussolution on mixing the components of the solution.

On use according to the invention of the mixing apparatus, 33.5 ml of1.5% strength active ingredient concentrate (PEG) and 430 ml of water(ratio 1:13) are combined by means of a Perfusor pump for theconcentrate and infusion pump for the diluting medium through the mixingapparatus so that a total volumetric flow of 434 ml/h is reached. Thisreduces the concentration of the organic solvent macrogol 400 in thecomplete mixture to 7%. The infusion volume needed to administer thedaily dose of 1000 mg of Bay 17-1648 in this case is 2×463.5 ml/day. Theinfusion time for a total of 1000 mg Bay 17-1648 in this case is 2×64min.

Mixer type — B Inlet pressure: diluting medium mbar 100 (DM) Inletpressure: active ingredient mbar 170 concentrate (AC) Solventconcentration (CM) g/100 ml¹⁾ 7 Active ingredient concentration in g/100ml²⁾ 1.5 the solvent Total amount of infused solvent ml 67 Dilutingmedium — water Volume of the complete mixture ml 927 (CM) Metering rate(total active mg/min 1000 mg/128 min ingredient dose) Volumetric flow CMml/h 434 Flow velocity: AC nozzle m/s 0.18 Flow velocity: DM nozzle m/s2.28 Flow velocity: CM aperture m/s 2.46 Particle count ≧ 10 μm Particlecount/ml 19 [max. 25/ml] Particle count ≧ 25 μm Particle count/ml 2[max. 3/ml] ¹⁾Mass of solvent based on 100 ml of complete solution;²⁾Mass of active ingredient based on 100 ml of solvent (activeingredient concentrate).

The saturation solubility of Bay 17-1648 with 7% PEG in water is about70 mg/100 ml. Compared with this value, the mixture ready for use is afactor of 1.5 supersaturated at 108 mg/100 ml. As the particlemeasurements show, the formulation is stable to crystallization for atleast 1 min.

EXAMPLE 4 Formulation of an Antibiotic of the Oxazolidinone Class (Bay34-7780) as 5% Strength Aqueous Active Ingredient Concentrate withAcidic pH

The antibiotic Bay 34-7780((5S)-3-[2-(3-pyridyl)pyridin-5-yl]-5-(methoxycarbonyl-aminomethyl)oxazolidin-2-onehydrochloride, EP-789026) as hydrochloride has a highly pH-dependentsolubility which allows only an acidic (pH 2.5) active ingredientconcentrate to be formulated. The saturation concentrations are asfollows:

Saturation con- pH centration 2.5 110 g/l 4 0.4 g/l

Formulation of a tolerated aqueous infusion solution with a pH of 4.0would accordingly be associated with an infusion volume of at least 2.51 for a daily dose of 1000 mg.

The only formulation which can be prepared for the desired daily dose of1000 mg with a maximum infusion volume of 500 ml has pH 2.5. This mustbe adjusted to a pH of at least 4.0 before administration. Exceeding thesaturation concentration by a factor of 5 in this case results incrystallization after standing for a short time.

The pKa of the active ingredient is 4.2 for a moderately strong acid.Utilization of 50% of the acid by addition of base adjusts the pH inaccordance with the Henderson-Hasselbalch equation to correspond to thepKa of 4.2.

On use according to the invention of the mixing apparatus, 20 ml of 5%strength aqueous active ingredient concentrate pH 2.5 and 480 ml ofsodium hydroxide solution pH 10.5 (ratio 1:24) are combined by means ofa Perfusor pump for the concentrate and infusion pump for the dilutingmedium through the mixing apparatus so that a total volumetric flow of500 ml/h is reached. This adjusts the pH of the solution to about pH 4.The infusion volume needed to administer the daily dose of 1000 mg ofBay 34-7780 is 500 ml/day. The infusion time in this case is 60 min for1000 mg of Bay 34-7780.

The saturation solubility of Bay 34-7780 at pH 4 is about 40 mg/100 ml.Compared with this value, the mixture ready for use is a factor of 5supersaturated at 200 mg/100 ml. A solution with a sufficientlywell-tolerated pH can be administered by the use according to theinvention of the homogenizing apparatus.

Mixer type — B Inlet pressure: dilutin medium mbar 120 (DM) Inletpressure: active ingredient mbar <100 concentrate (AC) Active ingredientconcentration in g/100 ml¹⁾ 5 the solvent Total amount of infusedsolvent ml 20 (pH 2.5) Dilutin medium — NaOH (pH 10.5) Volume of thecomplete mixture ml 500 (CM) Metering rate (total active mg/min 1000mg/60 min ingredient dose) Volumetric flow CM ml/h 500 Flow velocity: ACnozzle m/s 0.11 Flow velocity: DM nozzle m/s 2.72 Flow velocity: CMaperture m/s 2.83 Particle count ≧ 10 μm Particle count/ml 17 [max.25/ml] Particle count ≧ 25 μm Particle count/ml 1 [max. 3/ml] ¹⁾Mass ofactive ingredient based on 100 ml of solvent (active ingredientconcentrate).

EXAMPLE 5 Formulation of a Dihydropyridine (Bay y 5959, Ca Promoter)with Macrogol 400 as 0.5% Strength and 0.2% Strength Active IngredientConcentrate

The dihydropyridine Bay y 5959 (isopropyl(−)-(R)-2-amino-5-cyano-1,4-dihydro-6-methyl-4-(3-phenylquinolin-5-yl)pyridine-3-carboxylate,Ca promoter, EP-0 515 940 A1) is very slightly soluble in water at about0.1 μg/100 ml, but is readily soluble in macrogol 400 (PEG) at about 10g/100 ml.

Although a 30% strength PEG solution with an active ingredient contentof 100 mg/100 ml prepared in the conventional way without using themethod according to the invention and apparatus according to theinvention is stable to crystallization for 12 hours, therapeutic use ofBay y 5959 requires repeated administration over a period of 5 days. The30% concentration of PEG proved to be poorly tolerated by veins on thislong-term use. It is therefore necessary to limit the concentration oforganic solvents in the mixture for administration to a maximum of about15% PEG.

Solvent concentration 30% PEG Diluting medium water Active ingredientsaturation conc. in CM ca. 4 mg/100 ml (0.004%) Active ingredientconcentration in CM 100 mg/100 ml (0.1%) Supersaturation in CM ca.25-fold Amount of solvent per dose  30 g/100 mg Crystallization after 12h

EXAMPLE 5.1

On use according to the invention of the mixing apparatus, 20 ml of 0.5%strength active ingredient concentrate and 100 ml of water (ratio 1:5)are combined by means of a Perfusor pump for the concentrate andinfusion pump for the diluting medium through the mixing apparatus sothat a total volumetric flow of 180 ml/h is reached. This reduces theconcentration of the organic solvent macrogol 400 in the completemixture to 16.7%. The infusion volume needed to administer the dose of100 mg of Bay y 5959 in this case is 120 ml. The infusion time in thiscase is 40 min for 100 mg of Bay y 5959.

Mixer type — B Inlet pressure: diluting medium (DM) mbar <100 Inletpressure: active ingredient mbar <100 concentrate (AC) Solventconcentration (CM) g/100 ml¹⁾ 16.7 Active ingredient concentration inthe g/100 ml²⁾ 0.5 solvent Total amount of infused solvent ml 20Diluting medium — water Volume of the complete mixture ml 120 (CM)Metering rate (total active ingredient mg/min 100 mg/40 min dose)Volumetric flow CM ml/h 180 Flow velocity: AC nozzle m/s 0.17 Flowvelocity: DM nozzle m/s 0.85 Flow velocity: CM aperture m/s 1.02Particle count ≧ 10 μm [max. 25/ml] Particle count/ml 8 Particle count ≧25 μm [max. 3/ml] Particle count/ml 1 ¹⁾Mass of solvent based on 100 mlof complete solution; ²⁾Mass of active ingredient based on 100 ml ofsolvent (active ingredient concentrate).

EXAMPLE 5.2

In another example, 50 ml of 0.2% strength active ingredient concentrateand 283 ml of water (ratio 1:5.7) are combined by means of a Perfusorpump for the concentrate and infusion pump for the diluting mediumthrough the mixing apparatus so that a total volumetric flow of 200 ml/his reached. This reduces the concentration of the organic solventmacrogol 400 in the complete mixture to 15%. The infusion volume neededto administer the dose of 100 mg of Bay y 5959 in this case is 333 ml.The infusion time in this case is 100 min for 100 mg of Bay y 5959.

Mixer type — B Inlet pressure: diluting medium mbar <100 (DM) Inletpressure: active ingredient mbar <100 concentrate (AC) Solventconcentration (CM) g/100 ml¹⁾ 15 Active ingredient concentration ing/100 ml²⁾ 0.2 the solvent Total amount of infused solvent ml 50Diluting medium — water Volume of the complete mixture ml 333 (CM)Metering rate (total active mg/min 100 mg/100 min ingredient dose)Volumetric flow CM ml/h 200 Flow velocity: AC nozzle m/s 0.17 Flowvelocity: DM nozzle m/s 0.96 Flow velocity: CM aperture m/s 1.13Particle count ≧ 10 μm Particle count/ml 6 [max. 25/ml] Particle count ≧25 μm Particle count/ml 1 [max. 3/ml] ¹⁾Mass of solvent based on 100 mlof complete solution; ²⁾Mass of active ingredient based on 100 ml ofsolvent (active ingredient concentrate).

The supersaturation rates achieved with Bay y 5959 are as follows:

Solvent Active ingredient Active PEG amount (PEG) saturation ingredientSuper- per 100 mg concen- concentration concentration saturation activein- tration in CM in CM in CM gredient dose 30.0% 0.0040 g/100 ml 0.10g/100 ml 25-fold 30 g 16.7% ca. 0.0012 g/100 ml 0.08 g/100 ml 67-fold 21g 15.0% ca. 0.0012 g/100 ml 0.03 g/100 ml 25-fold 50 g CM = completemixture

The use according to the invention of the apparatus allows up to 67-foldsupersaturated infusion solutions to be used without the activeingredient crystallizing out in the administration system. In this casenot only is the solvent concentration reduced with an improvement in thelocal tolerability, but there is also a distinct reduction in the amountof solvent per dose, which increases the systemic tolerability.

EXAMPLE 6 Formulation of the Dihydropyridine Nifedipine (Adalat®) withMacrogol 400 as 0.2% Strength Active Ingredient Concentrate

Nifedipine is commercially available as an i.v. formulation as 0.01%strength aqueous solution with 15% ethanol and 15% macrogol 400 (PEG).The formulation is based on the low solubility of nifedipine in water.The use of ethanol and PEG means that the tolerability is not optimal,and approval in Japan is impossible because of the ethanol content.

Solvent concentration 30% (15% PEG + 15% ethanol) Diluting medium waterActive ingredient saturation conc. in ca. 42 mg/100 ml (0.042%) CMActive ingredient concentration in CM 10 mg/100 ml (0.1%)Supersaturation in CM none Amount of solvent per dose 15 g/5 mg (7.5 gPEG + 7.5 g ethanol) Crystallization none

The use according to the invention of the mixing apparatus makes itpossible, on formulating analogously to Example 5, to employ a solutionof nifedipine in PEG and to dispense with ethanol.

2.5 ml of 0.2% strength active ingredient concentrate and 25.5 ml ofwater (ratio 1:10) are combined by means of two Perfusor pumps throughthe mixing apparatus so that a total volumetric flow of 6.6 ml/h isreached. This reduces the concentration of the organic solvent PEG inthe complete mixture to 8.9%. The infusion volume needed to administerthe dose of 5 mg of nifedipine is 28 ml, in which case the infusion timeis 255 min, equivalent to a therapeutic dosage rate of about 1.2 mg/h.

Mixer type — A Inlet pressure: diluting medium (DM) mbar <100 Inletpressure: active ingredient mbar <100 concentrate (AC) Solventconcentration (CM) g/100 ml¹⁾ 8.9 Active ingredient concentration in theg/100 ml²⁾ 0.2 solvent Total amount of infused solvent ml 2.5 Dilutingmedium — water Volume of the complete mixture ml 28 (CM) Metering rate(total active ingredient mg/min 5 mg/255 min dose) Volumetric flow CMml/h 6.6 Flow velocity: AC nozzle m/s 0.02 Flow velocity: DM nozzle m/s0.21 Flow velocity: CM aperture m/s 0.23 Particle count ≧ 10 μm [max.25/ml] Particle count/ml 12 Particle count ≧ 25 μm [max. 3/ml] Particlecount/ml 1 ¹⁾Mass of solvent based on 100 ml of complete solution;²⁾Mass of active ingredient based on 100 ml of solvent (activeingredient concentrate).

It is possible in this case to obtain, after dilution to the useconcentration by using the apparatus, a 0.02% strength solution, that isto say twice as concentrated as the commercial formulation. A furtheradvantage is the possibility of achieving a solvent concentration of8.9%; this corresponds to a concentration reduction to one-thirdrelative to the commercial formulation. On use of the invention it isnecessary to infuse per 5 mg dose of nifedipine only 2.5 ml of macrogol400 compared with 7.5 g of macrogol and 7.5 g of ethanol for thecommercial product.

It was possible to show on the basis of the examples that the presentinvention has the following advantages:

1. Possibility of parenteral administration of slightly solublepharmaceuticals in high concentrations.

2. Possibility of reliable, reproducible and safe administration ofsupersaturated infusion solutions with which there is a great tendencyto crystallization of the active ingredient by in situ formulation.

3. Avoidance of the problem of the stability of supersaturatedsolutions.

4. Mixing of fluids at extremely low volumetric flows.

5. Mixing of fluids differing considerably in viscosity at lowvolumetric flows.

6. Reduction in the amount of excipients administered.

7. Complete avoidance of excipients or reduction in the concentrationthereof.

8. Reduction in the volume of organic solvents infused.

9. The small dimensions of the apparatus of the invention make directattachment to the patient possible.

What is claimed is:
 1. A method for the in situ formulation of amedicinal substance solution for parenteral administration, comprisingcontinuosly combining at least two metered part-streams with the aid ofa mixer to produce an active ingredient-containing solution as a totalvolumetric flow, characterized in that said solution is not inthermodynamic equilibrium, and said total volumetric flow after mixingis 0.2 ml/h to 500 ml/h.
 2. The method according to claim 1, wherein themixer includes a mixing chamber having a volume of 0.2 μl to 2 μl. 3.The method according to claim 2, wherein said mixer further comprises amixing section located downstream from said mixing chamber, and the timespent by the active ingredient containing solution in said mixingsection is less than 10 min.
 4. The method according to claim 3, whereinsaid time spent by the active ingredient containing solution in saidmixing section is less than 5 min.
 5. The method according to claim 2,wherein said mixing chamber has a volume of 0.4 μl to 1.5 μl.
 6. Themethod according to claim 1, wherein the metered part-streams compriseat least one active ingredient-containing solution and at least oneactive ingredient-free diluting medium, and the solution which is not inthermodynamic equilibrium is a supersaturated solution.
 7. The methodaccording to claim 6, wherein the active ingredient-containing solutionis an organic or aqueous organic active ingredient concentrate, and thediluting medium is an aqueous or aqueous organic diluting medium.
 8. Themethod according to claim 6, wherein said active ingredient containingsolution is an aqueous or aqueous organic active ingredient concentrate,said active ingedient-free diluting medium is an aqueous or aqueousorganic diluting medium, and the pH values of said concentrate and saiddiluting medium are matched together so that the total volumetric flowresulting after the mixing has a physiologically tolerated pH in therange from 3 to
 10. 9. The method according to claim 8, wherein saidtotal volumetric flow resulting after the mixing has a physiologicallytolerated pH in the range from 5-8.
 10. The method according to claim 6,wherein said active ingredient containing solution has a viscosity ≦500mPa.s and said aqueous active ingredient-free diluting medium has aviscosity in the range from 1 mPa.s to 0 mPa.s.
 11. The method accordingto claim 10, wherein active ingredient containing solution has aviscosity in the range from 50 mPa.s to 150 mPa.s and said aqueousactive ingredient-free diluting medium has a viscosity in the range from1 mPa.s to 10 mPa.s.
 12. The method according to claim 1, wherein onepart-stream contains active ingredient having a solubility of less than1% by weight in water at 20° C.
 13. The method according to claim 1,wherein the active ingredient is selected from the group consisting ofdihydropyridines, anaesthetics, antibiotics, antimycotics,immunosuppressants, CNS-active drugs, oncologicals, steroids,barbiturates and vitamins.
 14. The method according to claim 1, whereinpaclitaxel, docetaxel or substances related thereto, or cyclosporin, isused as active ingredient.
 15. The method according to claim 1, whereinsaid mixer is without dead spaces.
 16. The method according to claim 1,wherein said mixer is a nozzle mixer which comprises a) at least one setof opposing nozzles, each of said nozzles having a hydraulic diameterbetween 1 μm and 500 μm; b) a mixing chamber between said nozzles andhaving a volume of 0.2 μl to 2.0 μl; and c) a homogenizing aperturelocated downstream from and adjacent to said mixing chamber and having ahydraulic diameter between 1 μm and 500 μm; whereby each of saidpart-streams collides with the other in said mixing chamber, and theresulting active ingredient containing solution moves through saidhomogenizing aperture as said total volumetric flow.
 17. The methodaccording to claim 16, wherein the nozzle diameter is chosen so that theflow velocity in the nozzles is 0.01 to 15 m/s.
 18. The method accordingto claim 17, wherein said nozzle diameter is chosen so that the flowvelocity in the nozzles is 0.0 to 3 m/s.
 19. The method according toclaim 16, wherein said nozzles have a hydraulic diameter between 100 μmand 250 μm.
 20. The method according to claim 1, wherein said resultingtotal volumetric flow after mixing is 5 ml/h to 500 ml/h.
 21. Apparatusfor the in situ formulation of an active ingredient solution forparental administration, comprising a nozzle mixer which includes: a) afirst inlet, in the form of a nozzle having a hydraulic diameter between1 μm and 500 μm; b) a homogenizing aperture located downstream of saidfirst inlet and having a hydraulic diameter between 1 μm and 500 μm; c)a mixing chamber between said first inlet and said homogenizingaperture, and having a volume of 0.2 μl to 2 μl; d) at least one inletto said mixing chamber in addition to said first inlet; and e) a mixingsection located downstream of said homogenizing aperture and connectedto it.
 22. The apparatus according to claim 21 further comprising atleast two feed lines, in each of which a reservoir and a metering deviceare connected in series, each of said feed lines being connected to aninlet of said nozzle mixer; and an infusion line downstream of saidnozzle mixer and connected to said mixing section thereof.
 23. Theapparatus according to claim 22, wherein the flow pathways in the twofeed lines, including the metering devices and the nozzles, aresymmetrically designed.
 24. The apparatus according to claim 21, whereinthe mixer is made of an injection-moldable plastic.
 25. The apparatusaccording to claim 21, wherein said homogenizing aperture of the mixeris opposite to said nozzle.
 26. The apparatus according to claim 21wherein the additional inlet to said mixing chamber is in the form of anozzle having a hydraulic diameter of 1 μm to 500 μm.
 27. The apparatusaccording to claim 21, wherein said mixing chamber has a volume of 0.4μl to 1.5 μl, and said nozzle has a hydraulic diameter of 100 μm to 250μm.
 28. The apparatus according to claim 21, wherein said homogenizingaperture has a hydraulic diameter of 100 μm to 250 μm.
 29. The apparatusaccording to claim 21, wherein said mixer is made of polycarbonate. 30.An active ingredient administration kit for carrying out the methodaccording to claim 1, comprising apparatus according to claim 21 and areservoir with active ingredient concentrate.
 31. The active ingredientadministration kit according to claim 30, further comprising a reservoirwith diluting medium.
 32. The active ingredient administration kitaccording to claim 30, wherein further comprising tubing for theconnections to the apparatus and to the metering devices.
 33. The activeingredient administration kit according to claim 30, in which the activeingredient has a solubility of less than 1% by weight in water at 20° C.34. The active ingredient administration kit according to claim 30, inwhich the active ingredient is selected from the group consisting ofdihydropyridines, anaesthetics, antibiotics, antimycotics,immunosuppressants, CNS-active drugs, oncologicals, steroids,barbiturates and vitamins.
 35. An active ingredient administration kitaccording to claim 34, in which said active ingredient is paclitaxel,docetaxel or substances related thereto.
 36. The active ingredientadministration kit according to claim 34, in which said activeingredient is cyclosporin.